Copolymers of polyoxaamides

ABSTRACT

The present invention describes a polyoxaamide copolymer and blends thereof that may be used to produce hydrogels, surgical devices such as catheters, molded devices, and the like. The polyoxaamide copolymers of the present invention are composed of a first divalent repeating unit of formula IA: 
     
         [--X&#39;--C(O)--R.sub.30 --C(O)--]                            IA 
    
     a second divalent repeating unit of the formula IB: 
     
         [X--C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 
    
      --O--C(R 1 )(R 2 )--C(O)--]IB 
     and a third repeating unit selected from the group of formulas consisting of: 
     
         [--Y--R.sub.17 --].sub.T                                   II 
    
     
         [--O--R.sub.5 --C(O)--].sub.B,                             III 
    
     
         ([--O--R.sub.9 --C(O)].sub.P --O--).sub.L G                XI 
    
     and combinations thereof, wherein R 30  is an alkylene, arylene, arylalkylene, substituted alkylene, substituted arylene and substituted alkylarylene provided that R 30  cannot be --[C(R 1 )(R 2 )] 1--2  --O--R 3  --O--[C(R&#39; 1 )(R&#39; 2 )] 1--2  --; X, X&#39; and Y are selected from the group consisting of --O-- and --N(R)--, provided both X and Y are not both --O-- and may be blended with a second polymer that is preferably biocompatable.

This application is a continuation-in-part of application Ser. No.08/744,609 filed on Nov. 6, 1996 now U.S. Pat. No. 5,962,023, which is acontinuation-in-part of Ser. No. 08/611,532, filed Mar. 5, 1996, nowU.S. Pat. No. 5,597,579, which is a continuation-in-part of Ser. No.08/598,362, filed Feb. 8, 1996 now abandoned, which is acontinuation-in-part of Ser. No. 08/554,614, filed Nov. 6, 1995 nowabandoned, which is a continuation-in-part of Ser. No. 08/399,308, filedMar. 6, 1995, now U.S. Pat. No. 5,464,929.

FIELD OF THE INVENTION

The present invention relates to a polymeric material and moreparticularly to absorbable products made from copolymers ofpolyoxaamides and blends thereof with other polymers.

BACKGROUND OF THE INVENTION

Since Carothers early work in the 1920s and 1930s, aromatic polyesterparticularly poly(ethylene terephthalate) have become the mostcommercial important polyesters. The usefulness of these polymers isintimately linked to the stiffening action of the p-phenylene group inthe polymer chain. The presence of the p-phenylene group in the backboneof the polymer chain leads to high melting points and good mechanicalproperties especially for fibers, films and some molded products. Infact poly(ethylene terephthalate) has become the polymer of choice formany common consumer products, such as one and two liter soft drinkcontainers.

Several related polyester resins have been described in U.S. Pat. Nos.4,440,922, 4,552,948 and 4,963,641 which seek to improve upon theproperties of poly(ethylene terephthalate) by replacing terephthalicacid with other related dicarboxylic acids which contain phenylenegroups.

These polymers are generally designed to reduce the gas permeability ofaromatic polyesters.

Other aromatic polyesters have also been developed for specialtyapplications such as radiation stable bioabsorbable materials. U.S. Pat.Nos. 4,510,295, 4,546,152 and 4,689,424 describe radiation sterilizablearomatic polyesters that can be used to make sutures and the like. Thesepolymers like, poly(ethylene terephthalate), have phenylene groups inthe backbone of the polymers.

However, less research has been reported on aliphatic polyesters. AfterCarothers initial work on polyesters, aliphatic polyesters weregenerally ignored because it was believed that these materials had lowmelting points and high solubilities. The only aliphatic polyesters thathave been extensively studied are polylactones such as polylactide,polyglycolide, poly(p-dioxanone) and polycaprolactone. These aliphaticpolylactones have been used primarily for bioabsorbable surgical suturesand surgical devices such as staples. Although polylactones have provento be useful in many applications they do not meet all the needs of themedical community. For example films of polylactones do not readilytransmit water vapor, therefore, are not ideally suited for use asbandages where the transmission of water vapor would be desired.

Recently there has been renewed interest in non-lactone aliphaticpolyesters. U.S. Pat. No. 5,349,028 describes the formation of verysimple aliphatic polyesters based on the reaction of a diol with adicarboxylic acid to form prepolymer chains that are then coupledtogether. These polyesters are being promoted for use in fibers andmolded articles because these polyesters are biodegradable after theyare buried such as in a landfill. However, these materials are notdisclosed as being suitable for use in surgical devices.

To address the deficiencies in the polymers described in the prior artwe invented a new class of polymers which are disclosed in U.S. Pat.Nos. 5,464,929; 5,595,751; 5,597,579; 5,607,687; 5,618,552; 5,620,698;5,645,850; 5,648,088; 5,698,213; and 5,700,583 (all of which are herebyincorporated by reference). This new class of polymers is hydrolyzableand suitable for a variety of uses including medical applications. Tofurther broaden the possible uses for these polymers we are disclosingand claiming herein copolymers of the polyoxaamides (which includespolyoxaesteramides) and blends thereof with other polymers with modifiedhydrolysis profiles. These polymers may be used in industrial andconsumer applications where biodegradable polymers are desirable, aswell as, in medical devices.

SUMMARY OF THE INVENTION

We have discovered polyoxaamides copolymers and blends thereof withother polymers that may be used to produce a variety of useful productsincluding medical devices such molded devices, drug delivery matrices,coatings, lubricants and the like. The polyoxaamide copolymers of thepresent invention are copolymers comprising a first divalent repeatingunit of formula IA:

    [--X'--C(O)--R.sub.30 --C(O)--]                            IA

a second divalent repeating unit of the formula IB:

    [X--C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 --O--C(R'.sub.1)(R'.sub.2)--C(O)--]                       IB

and a third repeating unit selected from the group of formulasconsisting of:

    [--Y--R.sub.17 --].sub.T,                                  II

    [--O--R.sub.5 --C(O)--].sub.B,                             III

    ([--O--R.sub.9 --C(O)].sub.P --O--).sub.L G                XI

and combinations thereof, wherein R₃₀ is an alkylene, arylene,arylalkylene, substituted alkylene, substituted arylene and substitutedalkylarylene provided that R₃₀ cannot be --[C(R₁)(R₂)]₁₋₋₂ --O--R₃--O--[C(R'₁)(R'₂)]₁₋₋₂ --; X, X' and Y are selected from the groupconsisting of --O-- and --N(R)--, provided that X and Y cannot both be--O--; R, R₁, R'₁, R₂ and R'₂ are independently selected from the groupconsisting of hydrogen and an alkyl group containing 1 to 8 carbonatoms; R₃ is selected from the group consisting of an alkylene unit andan oxyalkylene group of the following formula: ##STR1## wherein C is aninteger in the range of from 2 to about 5, D is an integer in the rangeof from 0 to about 2,000, and E is an integer in the range of from about2 to about 5, except when D is zero, in which case E will be an integerin the range of from 2 to about 12; R₁₇ is a alkylene unit containingfrom 2 to 8 carbon atoms which may have substituted therein an internalether oxygen, an internal --N(R₁₈)-- or an internal --C(O)--N(R₂₁)--; Tis an integer in the range of from 1 to about 2,000 and preferably is inthe range of from 1 to about 1,000; R₁₈ and R₂₁ are independentlyselected from the group consisting of hydrogen and an alkyl groupcontaining 1 to 8 carbon atoms; R₅ and R₉ are independently selectedfrom the group consisting of --C(R₆)(R₇)--, --(CH₂)₃ --O--, --CH₂ --CH₂--O--CH₂ --, --CR₈ H--CH₂ --, --(CH₂)₅ --, --(CH₂)_(F) --O--C(O)-- and--(CH₂)_(K) --C(O)--CH₂ --; R₆ and R₇ are independently selected fromthe group consisting of hydrogen and an alkyl containing from 1 to 8carbon atoms; R₈ is selected from the group consisting of hydrogen andmethyl; F and K are independently selected integer in the range of from2 to 6; B is an integer in the range of from 1 to n such that the numberaverage molecular weight of formula III is less than about 200,000,preferably less than 100,000 and more preferably less than 40,000; P isan integer in the range of from 1 to m such that the number averagemolecular weight of formula XI is less than about 1,000,000, preferablyless than 200,000 and more preferably less than 40,000; G represents theresidue minus from 1 to L hydrogen atoms from the hydroxyl groups of analcohol previously containing from 1 to about 200 hydroxyl groups; and Lis an integer from about 1 to about 200; which have been crosslinked.

Additionally, the present invention describes a prepolymer comprising apolyoxaamide copolymer chemically linked to at least one polymerizableregion.

DETAILED DESCRIPTION OF THE INVENTION

The polyoxaamides copolymers (which also includes polyoxaesteramidesthat are within the scope of the present invention) of the presentinvention are the reaction product of 1) a dicarboxylic acid; 2) analiphatic alpha-oxydicarboxylic acid; and 3) a diamine or amino alcoholoptionally containing one of the following compounds: a diol (orpolydiol), a lactone (or lactone oligomer), a coupling agent orcombination thereof. For the purpose of this application aliphatic shallmean an organic compound having a straight, branched, or cyclicarrangement of carbon atoms (i.e. alkanes, olefins, cycloalkanes,cycloolefins and alkynes).

Suitable non-dioxycarboxylic acids may be polyfunctional for use in thepresent invention, generally have the following formula:

    HOOC--R.sub.30 --COOH                                      VA

wherein R₃₀ is an alkylene, arylene, arylalkylene, substituted alkylene,substituted arylene and substituted alkylarylene provided that R₃₀cannot be [--C(R₁)(R₂)]₁₋₋₂ --O-- R₃ --O--[C(R'₁)(R'₂)]₁₋₋₂ --; andthese non-dioxycarboxylic acids may be substituted with heteroatoms orgroups. The non-dioxycarboxylic acids of the present invention aregenerally polycarboxylic acids and more preferably dicarboxylic acids.However, monocarboxylic acids may be used as end caps for the polymerthat are formed. If carboxylic acids are used that have more than twocarboxylic acid groups the resulting polymers may form star shapes orcrosslinked matrices depending on the concentration of the carboxylicacids having more than two carboxylic acid groups.

Representative unsaturated aliphatic dicarboxylic acids include, but arenot limited to, those selected from the group consisting of maleic acid,fumaric acid and combinations thereof. Representative saturatedaliphatic dicarboxylic acids include, but are not limited to, thoseselected from the group consisting of oxalic acid, malonic acid(propanedioic), succinic (butanedioic), glutaric (pentanedioic), adipic(hexadioic), pimelic (heptanedioic), octanedioic, nonanedioic,decanedoic, undecanedioic, dodecanedioic, hendecanedioic,tetradecanedioic, pentadecanedioic, hexadecanedioic, heptadecandioic,octadecanedioic, nonadecanedioic, eicosanedioic acid and combinationsthereof. Representative aromatic dicarboxylic acids include, but are notlimited to, those selected from the group consisting of phthalic acid,isophthalic acid, terephthalic acid, phenylenediglycolic acid,caboxymethoxybenzoic acid and combinations thereof.

Suitable aliphatic alpha-oxydicarboxylic acids (or oxadicarboxylicacids) for formula IB generally have the following formula:

    HO--C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 --O--C(R'.sub.1)(R'.sub.2)--C(O)--OH                      VB

wherein R₁, R'₁, R and R'₂ are independently selected from the groupconsisting of hydrogen and an alkyl group containing from 1 to 8 carbonatoms and R₃ is an alkylene containing from 2 to 12 carbon atoms or isan oxyalkylene group of the following formula: ##STR2## wherein C is aninteger in the range of from about 2 to about 5, D is an integer in therange of from 0 to about 2,000 and preferably 1 to about 12, and E is aninteger in the range of from about 2 to about 5, except when D is zero,in which case E will be an integer in the range of from 2 to 12. Thesealiphatic alpha-oxydicarboxylic acids may be formed by reacting a diolor polydiol with an alpha-halocarboxylic acid such bromoacetic acid orchloroacetic acid under suitable conditions. In some instances thecorresponding mono or diester of the aliphatic alpha-oxydicarboxylicacids of formula V may be used.

Suitable amino alcohols, diamines, diols or polydiols for use in thepresent invention have repeating units with up to 8 carbon atoms havingthe formulas:

    H[--(N(R.sub.12)--R.sub.13 --).sub.U ]OH                   VIA

    H[--(N(R.sub.14)--R.sub.15 --).sub.V N(R.sub.16)           VIB

    H[--(O--R.sub.4 --).sub.A ]OH,                             VIC

    H[--(O--R.sub.19 --).sub.Z ]N(R.sub.20)H,                  VID

wherein R₁₃, R₁₅, R₄ and R₁₉ are independently alkylene units containingfrom 2 to 8 methylene units which may have substituted therein aninternal ether oxygen, an internal --N(R₁₈)-- or internal--C(O)--N(R₂₁)--; R₁₈ and R₂₁ are independently selected from the groupconsisting of hydrogen and an alkyl group containing 1 to 8 carbonatoms; R₁₂, R₁₄, R₁₆ and R₂₀ are independently selected from the groupconsisting of hydrogen, alkyl group containing from 1 to 8 carbon atomsand mixtures thereof; A, U, V and Z are independently integers in therange of from 1 to about 2,000 and preferably from 1 to 1,000. Examplesof suitable amino alcohols include amino alcohols selected from thegroup consisting of ethanol amine, isopropanol amine,3-amino-1-propanol, 4-amino-1-butanol, 4-amino-2-butanol,2-amino-1-butanol and 2-(2-aminoethoxy)ethanol. Examples of suitablediamines include diamines selected from the group consisting of ethylenediamine, 1,2-diaminopropane, 1,3-diaminopropane, 1,4-diaminobutane,1,4-diaminocyclohexane and 1,5-diamino-3-oxapentane. Examples ofsuitable diols include diols selected from the group consisting of1,2-ethanediol (ethylene glycol), 1,2-propanediol (propylene glycol),1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol,1,6-hexanediol, 1,4-cyclohexanediol, 1,8-octanediol and combinationsthereof. Examples of preferred polydiols include polydiols selected fromthe group consisting of polyethylene glycol (H[--O--CH₂ --CH₂ --]_(A)OH) and polypropylene glycol (H[--O--CH₂ --CH(CH₃)--]_(A) OH).

The ratio of aliphatic non-dioxycarboxylic acid to aliphaticoxydicarboxylic acid should be in the range of from about 1:99 to about99:1. The rate of hydrolysis can be controlled, in part, by changing theratio of the non-oxadiacid-based moeties to those of the oxadiacid-basedmoities. As the concentration of the non-oxadiacid-based moetiesincreases, the hydrolysis rate will be lower. Besides taking intoaccount the hydrophilic/hydrophobic nature of the reactants, one canalso exert control through the steric nature of the alcohol, amine, andamino alcohol groups employed. Thus the hydrolysis rate of an esterbased on a secondary alcohol is slower than that of an ester based on aprimary alcohol group. The relative concentration of polymeric amide(i.e. polyoxaamide concentration) to polymeric ester (i.e. polyoxaester)will also have an effect, as will the presence of aromatic moieties.Additionally, the presence of aromatic moieties will help resist theloss of properties that may occur during sterilization by gammairradiation. Higher concentrations of such groups will be better forcobalt sterilizable products.

The polymer produced by reacting the aliphatic non-dioxydicarboxylicacid and aliphatic oxydicarboxylic acid with the amino alcoholsdiscussed above should provide a polymer generally having the formula:

    [--[O--C(O)--R.sub.30 --C(O)--(N(R'.sub.12)--R'.sub.13).sub.U' ].sub.J' [--O--C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 --O--C(R'.sub.1)(R'.sub.2)--C(O)--(N(R.sub.12)--R.sub.13 --).sub.U --].sub.J" ].sub.J                                        VIIA

wherein R₁, R₂, R₃, R₁₂, R₁₃, U and U' are as described above; R'₁, R'₂,R'₁₂ and R'₁₃ have the same chemical definitions respectively as R₁, R₂,R₁₂, R₁₃ but may vary independently; J, J' and J" are independentintegers in the range of from about 1 to about 10,000 and preferably isin the range of from about 10 to about 1,000 and most preferably in therange of from about 50 to about 200.

The polymer produced by reacting the aliphatic non-dioxydicarboxylicacid and aliphatic oxydicarboxylic acid with the diamine discussed aboveshould provide a polymer generally having the formula:

    [[--N(R'.sub.16)--C(O)--R.sub.30 --C(O)--(N(R'.sub.14)--R'.sub.15).sub.V' ].sub.J' --[N(R.sub.16)--C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 --O--C(R'.sub.1)(R'.sub.2)--C(O)--(N(R.sub.14)--R.sub.15 --).sub.V --].sub.J" ].sub.J                                        VIIB

wherein R₁, R₂, R₃, R₁₄, R₁₅, R₁₆ V, and J are as described above andR'₁, R'₂, R'₁₄, R'₁₅, R'₁₆, V' and J' have the same definitionsrespectively as R₁, R₂, R₁₄, R₁₅, R₁₆, V and J but may varyindependently.

The polymer produced by reacting the aliphatic non-dioxydicarboxylicacid and aliphatic oxydicarboxylic acid with a mixture of aminoalcohols,diols and diamines discussed above should provide a polymer generallyhaving end groups that may be active amines or hydroxyl groups.

Suitable lactone monomers that may be used in the present inventiongenerally have the formula: ##STR3## These lactone monomers (orequivalent acids if any) may be polymerized to provide polymers of thefollowing general structures:

    H[--O--R.sub.5 --C(O)--].sub.B OH                          IX

    (H[--O--R.sub.9 --C(O)].sub.P --O--).sub.L G               X

wherein R₅ and R₉ are independently selected from the group consistingof --C(R₆)(R₇)--, --(CH₂)₃ --O--, --CH₂ --CH₂ --O--CH₂ --, --CR₈ H--CH₂--, --(CH₂)₅ --, --(CH₂)_(F) --O--C(O)-- and --(CH₂)_(K) --C(O)--CH₂ --;R₆ and R₇ are independently selected from the group consisting ofhydrogen and an alkyl containing from 1 to 8 carbon atoms; R₈ isselected from the group consisting of hydrogen and methyl; F and K areintegers in the range of from 2 to 6; B is an integer in the range offrom 1 to n such that the number average molecular weight of formula IXis less than about 200,000, preferably less than about 100,000, morepreferably less than about 40,000 and most preferably less than 20,000;P is an integer in the range of from 1 to m such that the number averagemolecular weight of formula X is less than about 1,000,000, preferablyless than about 200,000, more preferably less than about 40,000 and mostpreferably less than 20,000; G represents the residue minus from 1 to Lhydrogen atoms from the hydroxyl groups of an alcohol previouslycontaining from 1 to about 200 hydroxyl groups; and L is an integer fromabout 1 to about 200. Preferably G will be the residue of a dihydroxyalcohol minus both hydroxyl groups. Suitable lactone-derived repeatingunits may be generated from the following monomers include but are notlimited to lactone monomers selected from the group consisting ofglycolide, d-lactide, l-lactide, meso-lactide, ε-caprolactone,p-dioxanone, trimethylene carbonate, 1,4-dioxepan-2-one,1,5-dioxepan-2-one and combinations thereof.

The copolymer formed by reacting the above described amino alcohols,diamines, and diol (or polydiol) VI with the appropriate aliphaticdioxycarboxylic acid or aliphatic polydioxycarboxylic acid of formula Vaand Vb may also be copolymerized in a secondary ring-openingpolymerization with the lactone monomers XIII or in a condensationcopolymerization with the lactone oligomers IX or X, described above toform a copolymer generally of the formula: ##STR4## wherein X, X', Y andY' are selected from the group consisting of --O-- and N(R), providedthat X and Y cannot both be --O-- and X' and Y' cannot both be --O--; Sand S' are independently integers in the range of from about 1 to about10,000 and are preferably integers in the range of from about 1 to about1,000 and W is an integer in the range of from about 1 to about 1,000.These copolymers may be made in the form of random copolymers or blockcopolymers. To the compounds described above there may be added acoupling agent selected from the group consisting of trifunctional orhigher (i.e. tetrafunctional etc.) polyols, oxycarboxylic acids, andpolybasic carboxylic acids (or acid anhydrides thereof). The addition ofthe coupling agents causes the branching of long chains, which canimpart desirable properties in the molten state to the polyesterprepolymer. Examples of suitable polyfunctional coupling agents includetrimethylol propane, glycerin, pentaerythritol, malic acid, citric acid,tartaric acid, trimesic acid, propane tricarboxylic acid, cyclopentanetetracarboxylic anhydride, triethanol amine and combinations thereof.

The amount of coupling agent to be added before gelation occurs is afunction of the type of coupling agent used and the polymerizationconditions of the polyoxaamide copolymer or molecular weight of theprepolymer to which it is added. Generally in the range of from about0.1 to about 10 mole percent of a trifunctional or a tetrafunctionalcoupling agent may be added based on the moles of polyoxaamidecopolymers present or anticipated from the synthesis.

The preparation of the polyoxaamides copolymers (which also includespolyoxaesteramides) are preferably polymerizations performed under meltpolycondensation conditions at elevated temperatures. At times it may bepreferably to add a catalyst such as an organometallic compound.Preferred organometallic catalysts are tin-based catalysts e.g. stannousoctoate. The catalyst will preferably be present in the mixture at amole ratio of hydroxy groups, polydioxycarboxylic acid and optionallylactone monomer to catalyst will be in the range of from about 5,000 toabout 80,000/1. The reaction is preferable performed at a temperature noless than about 120° C. under reduced pressure. Higher polymerizationtemperatures may lead to further increases in the molecular weight ofthe copolymer, which may be desirable for numerous applications. Theexact reaction conditions chosen will depend on numerous factors,including the properties of the polymer desired, the viscosity of thereaction mixture, and the glass transition temperature and softeningtemperature of the polymer. The preferred reaction conditions oftemperature, time and pressure can be readily determined by assessingthese and other factors.

Generally, the reaction mixture will be maintained at about 220° C. Thepolymerization reaction can be allowed to proceed at this temperatureuntil the desired molecular weight and percent conversion is achievedfor the copolymer, which will typically take about 15 minutes to 24hours. Increasing the reaction temperature generally decreases thereaction time needed to achieve a particular molecular weight, but mayalso increase the extent of side reactions. We have found that reactionat about 220° C. to be generally suitable.

An alternative method of preparing the polyoxaamides copolymers involvesthe formation of a salt between the dioxycarboxylic acids of the presentinvention and multifunctional amines (i.e. diamines) with subsequentpolymerization of the salt.

In another embodiment, polyoxaamide copolymers can be prepared byforming a polyoxaamide prepolymer polymerized under meltpolycondensation conditions, then adding at least one lactone monomer orlactone prepolymer. The mixture would then be subjected to the desiredconditions of temperature and time to copolymerize the prepolymer withthe lactone monomers. If a lactone prepolymer is used, apolycondensation reaction can be used to increase the molecular weight.

The molecular weight of the prepolymer as well as its composition can bevaried depending on the desired characteristic, which the prepolymer isto impart to the copolymer. However, it is preferred that thepolyoxaamide prepolymers from which the copolymer is prepared have amolecular weight that provides an inherent viscosity between about 0.2to about 2.0 deciliters per gram (dl/g) as measured in a 0.1 g/dlsolution of hexafluoroisopropanol at 25° C. Those skilled in the artwill recognize that the polyoxaamide prepolymers described herein canalso be made from mixtures of more than one diol, amino alcohol, orcarboxylic acid.

One of the beneficial properties of the polyoxaamide copolymer made bythe process of this invention is that the ester linkages arehydrolytically unstable, and therefore the polymer is bioabsorbablebecause it readily breaks down into small segments when exposed to moistbodily tissue. By controlling the ratio of oxycarboxylic acid tononoxycarboxylic acid the hydrolysis rate of the resulting copolymer maybe tailored to the desired end product and end use.

The polyoxaamides copolymers of the present invention and thosedescribed in U.S. Pat. Nos. 5,464,929; 5,595,751; 5,597,579; 5,607,687;5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213; and 5,700,583 maybe blended together with other homopolymers copolymers and graftcopolymers to impart new properties to the material formed by the blend.The other polymers which the polyoxaamides may be blended with includebut are not limited to homopolymer and copolymer of lactone typepolymers with the repeating units described by Formula VIII, polyesters(such as adipates) aliphatic polyurethanes, polyether polyurethanes,polyester polyurethanes, polyethylene copolymers (such as ethylene-vinylacetate copolymers and ethylene ethyl acrylate copolymers), polyamides,polyvinyl alcohols, poly(ethylene oxide), polypropylene oxide,polyethylene glycol, polypropylene glycol, polytetramethylene oxide,polyvinyl pyrrolidone, polyacrylamide, poly(hydroxy ethyl acrylate),poly(hydroxyethyl methacrylate) absorbable polyoxalates, absorbablepolyanhydrides and combinations thereof. The copolymers (i.e. containingtwo or more repeating units) including random, block and segmentedcopolymers. Suitable lactone-derived repeating units may be generatedfrom the following monomers include but are not limited to lactonemonomers selected from the group consisting of glycolide, d-lactide,l-lactide, meso-lactide, ε-caprolactone, p-dioxanone, trimethylenecarbonate, 1,4-dioxepan-2-one, 1,5-dioxepan-2-one and combinationsthereof. The blends may contain about 1 weight percent to about 99weight percent of the polyoxaamides.

For some applications it may be desirable to add additional ingredientssuch as stabilizers, antioxidants radiopacifiers, fillers or the like.

The polyoxaamide copolymer and other polymers may be blended usingconventional mixing processes known in the art. For example a blend canbe prepared using a two-roll mill, an internal mixer (such as aBrabender or Banbury mixer), an extruder (such as a twin screw extruder)or the like.

The copolymers and blends of this invention can be melt processed bynumerous methods to prepare a vast array of useful devices. Thesecopolymer and blends can be injection or compression molded to makeimplantable medical and surgical devices, especially wound closuredevices. The preferred wound closure devices are surgical clips, staplesand sutures.

Alternatively, the copolymers and blends can be extruded to preparefibers. The filaments thus produced may be fabricated into varioustextile products such as yarns fibers, woven, non-woven, knitted orbraided materials including sutures or ligatures, attached to surgicalneedles, packaged, and sterilized by known techniques. The copolymers ofthe present invention may be spun as multifilament yarn and woven orknitted to form fabrics, scrims, or gauze, (or non-woven sheets may beprepared) or used in conjunction with other molded compressivestructures as composite materials. These composite structures may alsobe used in prosthetic devices within the body of a human or animal whereit is desirable that the structures have high tensile strength anddesirable levels of compliance and/or ductility. Useful embodimentsinclude tubes, including branched tubes, for artery, vein or intestinalrepair, nerve splicing, tendon splicing, sheets for typing up andsupporting damaged surface abrasions, particularly major abrasions, orareas where the skin and underlying tissues are damaged or surgicallyremoved.

Additionally, the copolymers and blends can be molded to form filmswhich, may be used as commercially as wrapping materials, bags, or canbe sterilized, and used in medical applications as a barrier material(skin covering or adhesion prevention devices). Another alternativeprocessing technique for the copolymers and blends of this inventionincludes solvent casting, particularly for those applications where adrug delivery matrix is desired.

In more detail, the surgical and medical uses of the filaments, films,and molded articles of the present invention include, but are notnecessarily limited to:

Knitted products, woven or non-woven, and molded products including:

a.

burn dressings

b.

hernia patches

c.

medicated dressings

d.

fascial substitutes

e.

gauze, fabric, sheet, felt or sponge for liver hemostasis

f.

gauze bandages

g.

arterial graft or substitutes

h.

bandages for skin surfaces

i.

suture knot clip

j.

orthopedic pins, clamps, screws, and plates

k.

clips (e.g.,for vena cava)

l.

staples

m.

hooks, buttons, and snaps

n.

bone substitutes (e.g., mandible prosthesis)

o.

intrauterine devices (e.g.,spermicidal devices)

p.

draining or testing tubes or capillaries

q.

surgical instruments

r.

vascular implants or supports

s.

vertebral discs

t.

extracorporeal tubing for kidney and heart-lung machines

u.

artificial skin and others

v.

catheters (including, but not limited to, the catheters described inU.S. Pat. No. 4,883,699 which is hereby incorporated by reference)

w.

scaffoldings and the like for tissue engineering applications

x.

adhesion prevention devices (felts, films, foams and liquids).

In another embodiment, the copolymers and blends (which includeprepolymers and suitable crosslinked polymers) can be used to coat asurface of an article (such as a surgical article to enhance thelubricity of the coated surface or deliver a pharmaceutically activecompound). The copolymer and blends may be applied as a coating usingconventional techniques. For example, the copolymers and blends may besolubilized in a dilute solution of a volatile organic solvent, e.g.acetone, methanol, ethyl acetate or toluene, and then the article can beimmersed in the solution to coat its surface. Once the surface iscoated, the article can be removed from the solution where it can bedried at room or elevated temperatures until the solvent and anyresidual reactants are removed.

For use in coating applications the copolymers and blends should exhibitan inherent viscosity (in the case of crosslinked polymers beforecrosslinking), as measured in a 0.1 gram per deciliter (g/dl) ofhexafluoroisopropanol (HFIP), between about 0.05 to about 2.0 dl/g,preferably about 0.10 to about 0.80 dl/g. If the final inherentviscosity were less than about 0.05 dl/g, then the copolymers and blendsmay not have the integrity necessary for the preparation of films orcoatings for the surfaces of various surgical and medical articles. Onthe other hand, although it is possible to use copolymers and blendswith an inherent viscosity (for crosslinkable polymers measured beforecrosslinking) greater than about 2.0 dl/g, it may be exceedinglydifficult to do so.

Although it is contemplated that numerous articles can be coated withthe copolymers and blends of this invention to improve the surfaceproperties of the article. Surgical article may also be coated withthese copolymers (including but not limited to endoscopic instruments).The preferred surgical articles to coat are stents, surgical sutures andneedles. The most preferred surgical article is a suture, mostpreferably attached to a needle. Preferably, the suture is a syntheticabsorbable suture. These sutures are derived, for example, fromhomopolymers and copolymers of lactone monomers such as glycolide,lactide, ε-caprolactone, 1,4-dioxanone, and trimethylene carbonate. Thepreferred suture is a braided multifilament suture composed ofpolyglycolide or poly(glycolide-co-lactide).

The amount of copolymer or blend to be applied on the surface of abraided suture can be readily determined empirically, and will depend onthe particular copolymer and suture chosen. Ideally, the amount ofcopolymer blend applied to the surface of the suture may range fromabout 0.5 to about 30 percent of the weight of the coated suture, morepreferably from about 1.0 to about 20 weight percent, most preferablyfrom 1 to about 5 weight percent.

If the amount of coating on the suture were greater than about 30 weightpercent, then it may increase the risk that the coating may flake offwhen the suture is passed through tissue.

Sutures coated with the copolymers and blends of this invention aredesirable because they have a more slippery feel, thus making it easierfor the surgeon to slide a knot down the suture to the site of surgicaltrauma. In addition, the suture can be passed more easily through bodytissue thus reducing tissue trauma. These advantages are exhibited incomparison to sutures which do not have their surfaces coated with thepolymers and blends of this invention.

In another embodiment of the present invention when the article is asurgical needle, the amount of coating applied to the surface of thearticle is an amount which creates a layer with a thickness rangingpreferably between about 2 to about 20 microns on the needle, morepreferably about 4 to about 8 microns. If the amount of coating on theneedle were such that the thickness of the coating layer was greaterthan about 20 microns, or if the thickness was less than about 2microns, then the desired performance of the needle as it is passedthrough tissue may not be achieved.

In yet another embodiment of the present invention, the copolymers andblends can be used as a pharmaceutical carrier in a drug deliverymatrix. To form this matrix the copolymers and blends would be mixedwith a therapeutic agent to form the matrix. The variety of differenttherapeutic agents that can be used in conjunction with the copolymersand blends of the present invention is vast. In general, therapeuticagents which may be administered via the pharmaceutical compositions ofthe invention include, without limitation: antiinfectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; and tranquilizers; andnaturally derived or genetically engineered proteins, polysaccharides,glycoproteins, or lipoproteins.

The drug delivery matrix may be administered in any suitable dosage formsuch as oral, parenteral, a subcutaneously as an implant, vaginally oras a suppository. Matrix formulations containing the copolymer andblends may be formulated by mixing one or more therapeutic agents withthe blends. The therapeutic agent may be present as a liquid, a finelydivided solid, or any other appropriate physical form. Typically, butoptionally, the matrix will include one or more additives, e.g.,nontoxic auxiliary substances such as diluents, carriers, excipients,stabilizers or the like. Other suitable additives may be formulated withthe copolymers and blends and pharmaceutically active agent or compound,however, if water is to be used it should be added immediately beforeadministration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001% to about 70%, more typically about0.001% to about 50%, most typically about 0.001% to about 20% by weightof the matrix.

The quantity and type of copolymers and blends incorporated into theparenteral will vary depending on the release profile desired and theamount of drug employed. The product may contain blends of copolymers ofdifferent molecular weights to provide the desired release profile orconsistency to a given formulation.

The copolymers and blends, upon contact with body fluids including bloodor the like, undergoes gradual degradation (mainly through hydrolysis)with concomitant release of the dispersed drug for a sustained orextended period (as compared to the release from an isotonic salinesolution).

This can result in prolonged delivery (over, say 1 to 2,000 hours,preferably 2 to 800 hours) of effective amounts (say, 0.0001 mg/kg/hourto 10 mg/kg/hour) of the drug. This dosage form can be administered asis necessary depending on the subject being treated, the severity of theaffliction, the judgment of the prescribing physician, and the like.

Individual formulations of drugs and polyoxaamide containing copolymersmay be tested in appropriate in vitro and in vivo models to achieve thedesired drug release profiles. For example, a drug could be formulatedwith a polyoxaamide copolymer and orally administered to an animal. Thedrug release profile could then be monitored by appropriate means suchas, by taking blood samples at specific times and assaying the samplesfor drug concentration. Following this or similar procedures, thoseskilled in the art will be able to formulate a variety of formulations.

The copolymers and blends of the present invention can be crosslinked toaffect mechanical properties. Crosslinking may either be chemically orphysical. Chemically crosslinked copolymer chains are connected bycovalent bonds, which can be formed by reactive groups contained on thepolymers, the addition of crosslinking enhancers and/or irradiation(such as gamma-irradiation). Physical crosslinking on the other handconnects the polymer chains through non-covalent bonds such as van derWaals interactions, hydrogen bonding or hydrophobic interactions. Inparticular, crosslinking can be used to control the water swellabilityof said invention.

In one embodiment, Formulas VII A and VII B may be endcapped with one ormore crosslinkable regions. Similarly, Formula XII and XIII may becrosslinked by attaching one or more polymerizable regions to an aminegroup.

The polymerizable regions are preferably polymerizable byphotoinitiation by free radical generation, most preferably in thevisible or long wavelength ultraviolet radiation. The preferredpolymerizable regions are acrylates, diacrylates, oligoacrylates,methacrylates, dimethacrylates, oligomethoacrylates, or otherbiologically acceptable photopolymerizable groups.

Other initiation chemistries may be used besides photoinitiation. Theseinclude, for example, water and amine initiation schemes with isocyanateor isothiocyanate containing macromers used as the polymerizableregions.

Useful photoinitiators are those that can be used to initiate by freeradical generation polymerization of the macromers without cytotoxicityand within a short time frame, minutes at most and most preferablyseconds. Preferred dyes, as initiators of choice for long wavelengthultraviolet (LWUV) or visible light initiation are ethyl eosin,2,2-dimethoxy-2-phenyl acetophenone, other acetophenone derivatives, andcamphorquinone. Crosslinking and polymerization may be initiated amongmacromers by a light activated free-radical polymerization initiatorsuch as 2,2-dimethoxy-2-phenyl acetophenone, other acetophenonederivatives, and camphorquinone. In other cases, crosslinking andpolymerization are initiated among macromers by a light-activatedfree-radical polymerization initiator such as2,2-dimethoxy-2-phenylacetophenone or a combination of ethyl eosin (10-⁴to 10-² M) and triethanol amine (0.001 to 0.1M), for example.

The choice of the photoinitiator is largely dependent on thephotopolymerizable regions. Although we do not wish to be limited byscientific theory, it is believed that the macromer includes at leastone carbon-carbon double bond, light absorption by the dye can cause thedye to assume a triplet state, the triplet state subsequently reactingwith the amine to form a free radical which initiates polymerization.Preferred dyes for use with these materials include eosin dye andinitiators such as 2,2-dimethyl-2-phenylacetophenone,2-methoxy-2-phenylacetophenone, and camphorquinone. Using suchinitiators, copolymers may be polymerized in situ by LWUV light or bylaser light of about 514 nm, for example.

Initiation of polymerization (crosslinking) is accomplished byirradiation with light at a wavelength of between about 200-700 nm, mostpreferably in the long wavelength ultraviolet range or visible range,320 nm or higher, most preferably about 514 nm or 365 nm.

There are several photooxidizable and photoreductible dyes that may beused to initiate polymerization (crosslinking). These include acridinedyes, for example, acriblarine; thiazine dyes, for example, thionine;xanthine dyes, for example, rose bengal; and phenazine dyes, forexample, nethylene blue. These are used with cocatalysis such as amines,for example, triethanolamine; sulphur compounds, for example, RSO₂ R¹ ;heterocycles, for example, imidazole; enolates; organometallics; andother compounds, such as N-phenyl glycine. Other initiators includecamphorquinones and acetophenone derivatives.

Thermal polymerization initiator systems may also be used. Thermalinitiators may be selected to allow polymerization (and/or crosslinking)to be initiated at a desired temperature. At times it may be desired touse a high temperature to initiate polymerization such as during amolding process. For many medical uses it will be desired to use systemsthat will initiate free radical polymerization at physiologicaltemperatures include, for example, potassium persulfate, with or withouttetramethyl ethylenediamine; benzoylperoxide, with or withouttriethanolamine; and ammonium persulfate with sodium bisulfite.

The crosslinked copolymers and blends (hereinafter copolymers) can beprocessed and used for many of the same uses as described heretofor. Inaddition, crosslinked copolymers are particularly well suited for theprevention of surgical adhesions, tissue adhesives, tissue coatings(i.e. sealants and the like) and in tissue engineering.

A preferred application is a method of reducing formation of adhesionsafter a surgical procedure in a patient. The method includes coatingdamaged tissue surfaces in a patient with an aqueous solution of alight-sensitive free-radical polymerization initiator and a macromersolution as described above. The coated tissue surfaces are exposed tolight sufficient to polymerize the macromer. The light-sensitivefree-radical polymerization initiator may be a single compound (e.g.,2,2-dimethoxy-2-phenyl acetophenone) or a combination of a dye and acocatalyst (e.g., ethyl eosin and triethanol amine).

Additionally, the copolymers (preferably crosslinked) can also be usedto form hydrogels, which are a three-dimensional network of hydrophiliccopolymers in which a large amount of water is present. In general theamount of water present in a hydrogel is at least 20 weight percent ofthe total weight of the dry copolymer. The most characteristic propertyof these hydrogels is that it swells in the presence of water andshrinks in the absence of water. The extent of swelling (equilibriumwater content) is determined by the nature (mainly the hydrophilicity)of the copolymer chains and the crosslinking density.

The kinetics of hydrogel swelling is limited by the diffusion of waterthrough the outer layers of the dried hydrogel. Therefore, whilehydrogels swell to a large extent in water, the time it takes to reachequilibrium swelling may be significant depending on the size and shapeof the hydrogel. To reduce the amount of time it takes for a hydrogel toreach equilibrium, hydrogel foams may be used. Hydrogels foams may bemade by crosslinking copolymers in the presence of gas bubbles. Thehydrogels foams prepared with macroscopic gas cells will have an opencelled structure similar to sponges except that the pore size willgenerally be an order of magnitude larger.

Hydrogels may be used for many of same uses that have been described forpolyoxaamides such as wound dressings materials, since the crosslinkedhydrogels are durable, non-antigenic, and permeable to water vapor andmetabolites, while securely covering the wound to prevent bacterialinfection. Hydrogels may also be used for coatings in general andmedical coatings in particular. The hydrogel coatings may provide asmooth slippery surface and prevent bacterial colonization on thesurface of the medical instrument. For example hydrogels may be used ascoatings on urinary catheter surfaces to improve its biocompatability.Hydrogels may also be used in a variety of applications where themechanical swelling of the hydrogel is useful such as in catheters as ablend component with a biocompatable elastomer (such as the elastomerdescribed in U.S. Pat. No. 5,468,253 hereby incorporated by reference).Additionally, hydrogels could be used for drug delivery orimmobilization of enzyme substrates or cell encapsulization. Other usesfor hydrogels have been described in the literature, many of which arediscussed in chapter one of Hydrogels and Biodegradable Polymers forBioapplications, published by the American Chemical Society (which ishereby incorporated by reference herein).

Crosslinking to form crosslinked structures can be performed in avariety of ways. For example the copolymers may be crosslinked whilebeing synthesized such as by utilizing a multifuncitonal monomers oroligomers. However, crosslinking at other times is also advantageous.For example crosslinking may be performed during the manufacture of adevice such by adding a thermal initiator to the copolymer prior toinjection molding a device. Additionally, crosslinking of apolymerizable region with a photoinitiator may be performed duringstereolithography to form devices. European Patent Application93305586.5 describes the process for performing stereolithography (withphotopolymerizable materials). As previously discussed photoinitiationmay be used in vivo to crosslink the polymers of the present inventionfor various wound treatments such as adhesion prevention and woundsealing. Coating may also be applied to devices and crosslinked in situto form films that will conform to the surface of the device.

In a further embodiment of the present invention the polyoxaamidecopolymers, copolymer blends, pre-crosslinked and post-crosslinkedcopolymers of the present invention can be used in tissue engineeringapplications as supports for cells. Appropriate tissue scaffoldingstructures are known in the art such as the prosthetic articularcartilage described in U.S. Pat. No. 5,306,311, the porous biodegradablescaffolding described in WO 94/25079, and the prevascularized implantsdescribed in WO 93/08850 (all hereby incorporated by reference herein).Methods of seeding and/or culturing cells in tissue scaffoldings arealso known in the art such as those methods disclosed in EPO 422 209 B1,WO 88/03785, WO 90/12604 and WO 95/33821 (all hereby incorporated byreference herein). Additionally, the crosslinkable prepolymers of thepresent invention can be used to encapsulate cells for tissueengineering purposes.

The Examples set forth below are for illustration purposes only, and arenot intended to limit the scope of the claimed invention in any way.Numerous additional embodiments within the scope and spirit of theinvention will become readily apparent to those skilled in the art.

EXAMPLE 1

Preparation of 3,6-Dioxaoctanedioic Acid and Its Dimethylester

The diacid, 3,6-dioxaoctanedioic acid, was synthesized by oxidation oftriethylene glycol. The oxidation was carried ##STR5## out in a 500milliliter, three-neck round bottom flask equipped with a thermometer,an additional funnel, a gas absorption tube and a magnetic spinbar. Thereaction flask was lowered into an oil bath resting upon a magneticstirrer. To the reaction flask was added 157.3 ml of a 60% nitric acidsolution; 37.0 g of triethylene glycol was added to the additionalfunnel. The contents of the flask were heated to 78-80° C. A test tubecontaining 0.5 g of glycol and one milliliter of concentrated nitricacid was warmed in a water bath until brown fumes started appearing. Thecontents were then added to the reaction flask. The mixture was stirredfor a few minutes; the glycol was then carefully added. The rate ofaddition had to be monitored extremely carefully to keep the reactionunder control. The addition rate was slow enough so that the temperatureof the exothermic reaction mixture was maintained at 78-82° C. After theaddition was completed (80 minutes), the temperature of the reactionmixture was maintained at 78-80° C. for an additional hour. Whilecontinuing to maintain this temperature range, the excess nitric acidand water was then distilled off under reduced pressure (water suction).The syrupy residue was cooled; some solids appeared. The reactionproduct had the IR and NMR spectra expected for the dicarboxylic acid;the crude product was used as such for esterification.

The crude diacid could be purified to the extent needed forpolymerization or alternately could be converted to the correspondingdiester, the diester purified and subsequently hydrolyzed back to(purified) diacid. In yet another mode of purification, the diaminesalts of the diacids are purified and then subsequently polymerized toform the polyoxaamides of the present invention.

Esterification of the crude 3,6-dioxaoctanedioic acid was accomplishedas follows: To the reaction flask containing 36 g of the crude diacid,was added 110 ml of methanol. This was stirred for 3 days at roomtemperature after which 15 g of sodium bicarbonate was added and stirredovernight. The mixture was filtered to remove solids. To the liquor wasadded an additional 10 g of sodium bicarbonate; this mixture was stirredovernight. The mixture was again filtered; the liquor was fractionallydistilled. NMR analysis of the esterified product showed a mixture ofdimethyl triglycolate (78.4 mole %) and monomethyltriglycolate (21.6mole %). No significant condensation of diacid was observed.

EXAMPLE 2

Preparation of Polyoxaesteramide From 3,6-dioxaoctanedioic Acid andEthanolamine ##STR6##

A flame dried, mechanically stirred, 50-milliliter glass reactorsuitable for polycondensation reaction, is charged with the equivalentof 0.1 mole of purified 3,6-dioxaoctanedioic acid from Example 1 (17.81g), and 0.1 mole of ethanolamine (6.11 g). This generally could be doneby charging the reactor with exact stoichometric amounts of the diacidand the amino alcohol; alternately a small excess of ethylene glycol canbe substituted for a portion of the amino alcohol. The polymerizationcan be conducted without additional catalyst or alternately a smallamount of catalyst (eg. 0.0606 ml of a solution of 0.33 M stannousoctoate in toluene) can be added. After purging the reactor and ventingwith nitrogen, the temperature is gradually raised over the course of 26hours to 180° C. A temperature of 180° C. is then maintained for another20 hours; all during these heating periods under nitrogen at oneatmosphere, the water formed is collected. The reaction flask is allowedto cool to room temperature; it is then slowly heated under reducedpressure (0.015-1.0 mm) over the course of about 32 hours to 160° C.,during which time additional distillates can be collected. A temperatureof 160° C. is maintained for 4 hours after which a sample, a few gramsin size, of the polymer formed is taken. The sample is found to have aninherent viscosity (I.V.) of approximately 0.2 dl/g, as determined inhexaflouroisopropanol (HFIP) at 25° C. at a concentration of 0.1 g/dl.The polymerization is continued under reduced pressure while raising thetemperature, in the course of about 16 hours, from 160° C. to 180° C.; atemperature of 180° C. is maintained for an additional 8 hours, at whichtime a polymer sample is taken and found to have an I.V. ofapproximately 0.3 dl/g. The reaction is continued under reduced pressurefor another 8 hours at 180° C. The resulting polymer should have aninherent viscosity of approximately 0.4 dl/g, as determined in HFIP at25° C. and at a concentration of 0.1 g/dl.

EXAMPLE 3

Preparation of Polyoxaamide With 3,6,9-trioxaundecanedioic Acid andEthylene Diamine ##STR7##

A flame dried, mechanically stirred, 250-milliliter glass reactor,suitable for polycondensation reaction, is charged with the equivalentof 0.2 mole (44.44 g) of 3,6,9-trioxaundecanedioic acid, and 0.2 mole(12.02 g) of ethylene diamine; this can be conveniently done by chargingthe reactor with the stoichometric salt formed between the diacid andthe diamine. Alternately a small excess of ethylene glycol can besubstituted for a portion of the diamine. The polymerization can beconducted without additional catalyst or alternately a small amount ofcatalyst (eg. 0.0606 ml of a solution of 0.33M stannous octoate intoluene or 10 milligrams of dibutyltin oxide) can be added.

After purging the reactor and venting with nitrogen, the contents of thereaction flask are gradually heated under nitrogen at one atmosphere, inthe course of about 32 hours, to 180° C., during which time the waterformed is collected. The reaction mass is allowed to cool to roomtemperature. The reaction mass is then heated under reduced pressure(0.015-1.0 mm), gradually increasing the temperature to 180° C. in about40 hours; during this time additional distillates is collected. Thepolymerization is continued under reduced pressure while maintaining180° C. for an additional 16 hours. The resulting polymer should have aninherent viscosity of approximately 0.5 dl/g as determined in HFIP at25° C. and at a concentration of 0.1 g/dl.

EXAMPLE 4

Preparation of Polyoxaamide With Polyglycol Diacid and Jeffamine##STR8##

A flame dried, mechanically stirred, 500-milliliter glass reactor(suitable for polycondensation reaction) is charged with the equivalentof 0.2 mole (123.8 g) of polyglycol diacid (molecular weight about 619),and 0.2 mole (117.7 g) of Jeffamine (amine terminated polyethyleneoxide). This generally could be done by charging the reactor withstoichometric amounts of the diacid and the diamine or by charging thecorresponding preformed salt of the diacid and diamine. As an alternateprocess, a small excess of ethylene glycol can be substituted for aportion of the diamine. The polymerization can be conducted withoutadditional catalyst or alternately a small amount of catalyst. Afterpurging the reactor and venting with nitrogen, the contents of thereaction flask is heated under nitrogen at one atmosphere, graduallyincreasing the temperature to 200° C. in about 32 hours; during thistime the water formed is collected. The reaction flask is heatedgradually under reduced pressure (0.015-1.0 mm) from room temperature to140° C. in about 24 hours, during which time additional distillates arecollected. A polymer sample of about ten grams is taken at this stage,and found to have an I.V. of approximately 0.1 dl/g in HFIP at 25° C.,0.1 g/dl. The polymerization is continued under reduced pressure whileheating from 140° C. to 180° C. in about 8 hours, and then maintained at180° C. for an additional 8 hours. The reaction temperature is thenincreased to 190° C. and maintained there under reduced pressure for anadditional 8 hours. The resulting polymer should have an inherentviscosity of approximately 0.6 dl/g as determined in HFIP at 25° C. andat a concentration of 0.1 g/dl.

EXAMPLE 5

Preparation Of Polyoxaester Based On Polyglycol Diacid With PolyethyleneGlycol

To a flame-dried, 250-ml, 2-neck flask suitable for polycondensationreaction, 15.13 grams of polyglycol diacid (m.w. 619 g/m; 0.02444 mole),15.0 grams polyethylene glycol (m.w. 600 g/m; Aldrich, 0.025 mole), 3.18grams ethylene glycol (m.w. 62.07 g/m, 0.0512 mole were charged, anddried over night under high vacuum at room temperature. The next day,2.5 mg of dibutyl tin oxide (m.w. 248.92) was added. The reaction mass,under nitrogen at one atmosphere, was then gradually heated to 200° C.over a period of 16 hours while collecting the distillate. The reactionflask was allowed to cool to room temperature and the pressure reduced.Now under vacuum, it was gradually heated to 180-200° C., and run atthis temperature until the desired molecular weight was obtained. Theresulting copolymer has an I.V. of 0.63 dl/g.

EXAMPLE 6

Preparation of Polyoxaester Hydrogel Based on Polyglycol Diacid withPolyethylene Glycol

To a flame-dried, 250 ml, 2 neck flask, suitable for polycondensationreaction, 77.34 grams of polyglycol diacid (m.w. 619; 0.125 mole), 63.60grams of polyethylene glycol (m.w. 600; Aldrich, 0.106 mole), 15.52grams of ethylene glycol (m.w. 62.07; 0.250 mole), and 2.55 grams oftrimethylol propane (m.w. 134.18; 0.019 mole) were charged and driedover night under high vacuum at room temperature. The next day, 12.5 mgof dibutyl tin oxide (m.w 248.92) was charged. The reaction mass, undernitrogen at one atmosphere, was then gradually heated to 190-200° C.over a period of 16 hours while collecting the distillate. The reactionflask was allowed to cool to room temperature and the pressure reduced.Now under vacuum, it was gradually heated to 170° C. and maintainedthere about 22 hours. The resulting viscous polymer was transferred intoa tray for devolatalized in a vacuum oven until a film formed. Theresulting film was light brown in color. It swelled in water and wasfound to disappeared in about two weeks.

EXAMPLE 7

Preparation Of Copolymers of Polyoxaester Based On Adipic and PolyglycolDiacids with Polyethylene Glycol

The following is an example of how a copolymer of polyoxaester could beprepared. To a flame-dried, 250-ml, 2-neck flask suitable forpolycondensation reaction, 15.13 grams of polyglycol diacid (m.w.619g/m; 0.02444 mole), 0.893 grams of adipic acid (m.w. 146.14 g/m;0.00611 mole), 15.0 grams polyethylene glycol (m.w. 600 g/m; Aldrich,0.025 mole), 3.18 grams ethylene glycol (m.w. 62.07 g/m, 0.0512 mole canbe charged, and dried over night under high vacuum at room temperature.The next day, a suitable catalyst at a suitable level (i.e. 2.5 mg ofdibutyl tin oxide) can be added. The reaction mass, under nitrogen atone atmosphere, can then be gradually heated to 200° C. over a period of16 hours while collecting the distillate. The reaction flask can beallowed to cool to room temperature and the pressure reduced. Now undervacuum, it can be gradually heated to elevated temperatures (i.e.180-200° C. or higher) and kept at elevated temperatures until thedesired molecular weight is obtained. The ester moieties of theresultant copolymer are approximately 20% adipate in nature. Althoughthe initial charge is rich, on a mole basis, in ethylene glycol, thediol based moieties in the resultant copolymer are much richer inpolyethylene glycol-based moieties due to differences in relativevolatility.

EXAMPLE 8

Preparation of Copolymers of Polyoxaamide Based on Adipic and3,6-Dioxaoctanedioic Acids with Hexamethylene Diamine

The following is an example of how a copolymer of polyoxaamide could beprepared. To an autoclave capable of operation at 200 to 300 psi, 22.1grams of the hexamethylene diamine salt of 3,6-dioxaoctanedioic acid(m.w. 276.334 g/m; 0.08 mole) and 4.89 grams of the hexamethylenediamine salt of adipic acid (m.w. 244.335 g/m; 0.02 mole) are added.Alternately, aqueous solutions of these salts can be added. A keyrequirement is the removal of water while minimizing the loss of diamineas the reaction mixture is heated to elevated reaction temperatures. Asthe temperature increases, so does the pressure. The pressure is slowlyreduced to atmospheric pressure. The reaction can be allowed to continueat atmospheric pressure or alternately at reduced pressure to achievehigher molecular weight. Suitable reaction temperatures allow thereaction to proceed at a convenient rate without significantdegradation.

We claim:
 1. A polyoxaamide copolymer comprising a polyoxaamidecopolymer having a first divalent repeating unit of formula IA:

    [--X'--C(O)--R.sub.30 --C(O)--]                            IA

a second divalent repeating unit of the formula IB:

    [X--C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 --O--C(R'.sub.1)(R'.sub.2)--C(O)--]                       IB

and a third repeating unit selected from the group of formulasconsisting of:

    [--Y--R.sub.17 --].sub.T                                   II

    [--O--R.sub.5 --C(O)--].sub.B,                             III

    [--O--R.sub.9 --C(O)].sub.P --O--).sub.L G                 XI

and combinations thereof, wherein R₃₀ is an alkylene, arylene,arylalkylene, substituted alkylene, substituted arylene and substitutedalkylarylene provided that R₃₀ cannot be --[C(R₁)(R₂)]₁₋₋₂ --O--R₃--O--[C(R'₁)(R'₂)]₁₋₋₂ --; X, X' and Y are selected from the groupconsisting of --O-- and --N(R)--, provided that X, X' and Y cannot bothbe --O--; R, R₁, R'₁, R₂ and R'₂ are independently selected from thegroup consisting of hydrogen and an alkyl group containing 1 to 8 carbonatoms; R₃ is selected from the group consisting of an alkylene unit andan oxyalkylene group of the following formula: ##STR9## wherein C is aninteger in the range of from 2 to about 5, D is an integer in the rangeof from 0 to about 2,000, and E is an integer in the range of from about2 to about 5, except when D is zero, in which case E will be an integerin the range of from 2 to 12; R₁₇ is an alkylene unit containing from 2to 8 carbon atoms which may have substituted therein an internal etheroxygen, an internal --N(R₁₈)-- or an internal --C(O)--N(R₂₁)--; T is aninteger in the range of from 1 to 2,000; R₁₈ and R₂₁ are independentlyselected from the group consisting of hydrogen and an alkyl groupcontaining 1 to 8 carbon atoms; R₅ and R₉ are independently selectedfrom the group consisting of --C(R₆)(R₇)--, --(CH₂)₃ --O--, --CH₂ --CH₂--O--CH₂ --, --CR₈ H--CH₂ --, --(CH₂)₅ --, --(CH₂)_(F) --O--C(O)-- and--(CH₂)_(K) --C(O)--CH₂ --; R₆ and R₇ are independently selected fromthe group consisting of hydrogen and an alkyl containing from 1 to 8carbon atoms; R₈ is selected from the group consisting of hydrogen andmethyl; F and K are independently selected integer in the range of from2 to 6; B is an integer in the range of from 1 to n such that the numberaverage molecular weight of formula III is less than about 200,000; P isan integer in the range of from 1 to m such that the number averagemolecular weight of formula XI is less than about 1,000,000; Grepresents the residue minus from 1 to L hydrogen atoms from thehydroxyl groups of an alcohol previously containing from 1 to about 200hydroxyl groups; and L is an integer from about 1 to about
 200. 2. Thepolyoxaamide copolymer of claim 1 wherein the number average molecularweight of formula III contained in the polyoxaamide is less than100,000.
 3. The polyoxaamide copolymers of claim 1 wherein thepolyoxaamide copolymer has the formula: ##STR10## wherein Y' and X' areselected from the group consisting of --O-- and N(R); R₄ and R'₄ areindependently selected from alkylene groups containing from 2 to 8carbon atoms which may be substituted with an internal ether oxygen aninternal --N(R₁₈)-- or an internal --C(O)--N(R₂₁)--; A' is integer inthe range of from 1 to about 2,000; S' and S" are independently integersin the range of from about 1 to about 10,000 and W is an integer in therange of from about 1 to about 1,000.
 4. The polyoxaamide copolymers ofclaim 1 wherein the polyoxaamide copolymer has the formula:

    [[--X'--(R'.sub.4 --Y').sub.A' --C(O)--R.sub.30 --C(O)].sub.S' [--(X--(R.sub.4 --Y).sub.A --C(O)--C(R.sub.1)(R.sub.2)--O--R.sub.3 --O--C(R'.sub.1)(R'.sub.2)--C(O)].sub.S" (--[--O--R.sub.9 --C(O)].sub.P --O--).sub.L G].sub.W                                     XIII

wherein Y' and X' are selected from the group consisting of --O-- andN(R); R₄ and R'₄ are independently selected from alkylene groupscontaining from 2 to 8 carbon atoms which may be substituted with aninternal ether oxygen an internal --N(R₁₈) or an internal--C(O)--N(R₂₁)--; A' is integer in the range of from 1 to about 2,000;S' and S" are independently integers in the range of from about 1 toabout 10,000 and W is an integer in the range of from about 1 to about1,000.
 5. The polyoxaamide copolymer of claim 1 wherein the polyoxaamidecopolymer is linked to one or more polymerizable regions.
 6. Thepolyoxaamide copolymer of claim 1 wherein the polyoxaamide copolymer hasbeen crosslinked.
 7. The polyoxaamide copolymer of claim 6 wherein thepolyoxaamide copolymer has been crosslinked by the addition of acoupling agent.
 8. The polyoxaamide copolymer of claim 1 wherein thecrosslinked polyoxaamide copolymer has been contacted with water to forma hydrogel.
 9. The polyoxaamide copolymer of claim 1 wherein thepolyoxaamide copolymer contains as a third repeat unit a lactone derivedrepeating unit derived from lactone monomers selected from the groupconsisting of glycolide, d-lactide, l-lactide, meso-lactide,ε-caprolactone, p-dioxanone, trimethylene carbonate, 1,4-dioxepan-2-one,1,5-dioxepan-2-one and combinations thereof.